Preparation of 9, 11-oxido-steroids



United statesmen 2,838,493 -l-fli l 'if Jane 19 195-8 PREPARATION OF9,11-OXiDO-STEROIDS Robert P. Graber, Elizabeth, and Calvin Stewartshoddy; Jr., Plainlield, N. J., assignors to Merck & Co., Inc., Rahway,N. L, a corporation of New Jersey No Drawing. Application January 5,1955 Serial No. 480,054

5 Claims. (Cl. 260--23.55)

This invention relates to steroids and particularly to the preparationof 9 3,115-oxido-steroids.

I 1t has been proposed to prepare 21-esters of 9a-fluoro- 4-pregnene-113,l7a,21-trio1-3,20-dione (9a-fluoro-hydrocortisone) from thecorresponding 9a-bromo-steroid by first reacting it with potassiumacetate to form the 'corresponding 21-ester of95,11fl-oxido-4-pregnene-1706,21- diol-3,20-dione and then treating thiscompound with hydrogen fluoride. The reaction'with potassium acetateresults in the formation of a large amount of impurities one of which isthe 21-ester of 4-pregnene-17,21-di0l-3, 11,20-trione. The eventualremoval of these impurities, and particularly the 2l-ester of4-pregnene-17u,21-diol- 3,11,20-trione (cortisone), from the 21-ester of9-fluorohydrocortisone involves a laborious and difficult separationtechnique and correspondingly results in relatively low yields.

. An object of the invention is to produce 9 3,l1 3-oxidosteroids inrelatively pure form without the formation of undesirable products.Another object of the invention is to produce 95,11fi-oxido-steroidsfrom the corresponding 9a-bromo-llfi-hydroxy steroid in high yield.Other objects and the advantages of the invention will appearhereinafter.

In accordance with the invention 95,11fl-oxido-steroids are produced byreacting a 90t-bIOIllO-11fl-hydIOXY steroid with a strong base. Thisreaction substantially eliminates formation of the undesiredll-keto-steroid and results in an increase in yield of the desired9fi,l1,8-oxido-steroid. By the term strong base is meant a substancewhich will exhibit a pH greater than about 10 when in an aqueoussolution of one-tenth of one percent concentration at a temperature ofapproximately 27 C. The pH is conveniently measured on a Beckmann pHmeter such as Model G.

Typical examples of suitable strong bases are alkali and alkaline earthmetal alkoxides and hydroxides, alkali metal carbonates, and quarternaryammonium hydroxides. The alkoxid es are'preferably those containing fromone to eight carbon atoms. Particular examples of strong bases aresodium methoxide, potassium-t-butoxide, potassium ethoxide, sodiumhydroxide, potassium hydroxide, sodium ethoxide, tetramethyl ammoniumhydroxide, tetraethyl ammonium hydroxide, methyltriethyl ammoniumhydroxide, calcium isopropoxide, magnesium methoxide,magnesium'hydroxide, barium hydroxide, barium methoxide,

sodium carbonate, potassium carbonate, lithium carbonsuch .as at the4,5,6 and/or 16 positions, an 18 aldehydo group, and ethylenedioxygroups such as at the 3 and/or 20 p0sitions, do not interfere with thereaction. A 21- ester group such as the acetate, propionate, formate,butyrate, benzoate, t-butyl-acetate, hemisuccinate and phenylacetategroup also does not interfere with the reaction but is removed duringthe reaction. In certain cases it may be desirable to acylate thereaction product to convert the saponfied material back to the esterform. Typical examples of such compounds are 9u-bromo-4- pregnene 11B o13 one; 911 bromo 4 pregnene- 1'1,6,l7a diol 3 one; bromo 4 pregnene 113, 21- diol 3 one; 90: bromo 4- pregnene 115,200, 21 tn'ol 3fone; 9abromo 4 pregnene 11B,

17 ,20,2l tetrol 3 one; 90: bromo 4 pregnene- 11,8,l7a,20fl,2l tetrol 3one; 90: bromo 4 -preg nene o1 3,20 dione 91x.- bromo 4 pregnene-1113,1700 diol 3,20 dione; 9a bromo 4 pregnenel1/i,2l diol 3,20' -'dione(2l-acetate and other 21 esters); 9a bromo 4 pregnene 11fl,17oa,21triol- 3,20 dione; 9a bromo 4 pregnene 11/3,l7u,21- triol 3,20 dione 21formate; 9a bromo 4 pregnene 11,8,17a,21 triol 3,20 dione 21 acetate; 9abromo 4 pregnene 1lfi,l7oc,2l triol-3,20- dione 21 propionate; 90c bromo4 pregnene 115, 17oc,21 triol 3,20 dione 21 butyrate; 9a bromo 4pregnene 11fi,17ot,21 triol 3,20 dione 21 benzoate; 9a bromo 4 pregnene1ll3,17a,21 triol 3,20- dione 21 t butyl acetate; 90: bromo 4 pregnene-11B,17a,21 triol 3,20 dione ZI-hemisuccinate; 9abromo 4 pregnene11fi,17a,21 triol 3,20 dione 21 phenylacetate; 9a bromo 4 pregnene 11,901- 3,6 dione;;9u bromo 4 pregnene 116 01 -.3,6 2.0 trione; 90c bromo 4pregnene 11/3,17oz diol- 3,6,20 trione; 9a bromo 4 pregnene l1;8,17a,21-triol 3,6,20 trione; 90c bromo 4 pregnene 11,9, 21 diol 3,6,20 trione;90c bromo 4 pregnene- 6u,l1}9 diol 3,20 dione; 9a bromo 4 pregnene-6,B,11, 3 diol 3,20 dione; 90c bromo 4 pregnene- 4,l1;3 diol 3,20 dione;9oz bromo 4 pregnene- 4,11B,17u-triol 3,20 dione; 9a-bromo 4 pregnene-4,11fi,17u,21 tetrol 3,20 dione; 9a bromo 4- pregnene l1p,17a,21 triol3,6,20 trione 21 acetate; 9a bromo 4 pregnene 4,11fi,17a,21 tetrol 3,20dione, 4,21 diacetate; 9a bromo 4 pregnene 11B- ol 3- one; 9oz bromo 4pregnene 115,170: diol- 3 one; 90 bromo 4 pregnene 11B ol 3,20-

dione; 9a bromo pregnene 11fl,170c-di0l 3,20 dione;

9a bromo pregnane 11,6,17a,21 triol 3,20 dione; 9a bromo pregnane 11B,21diol 3,20 dione; 900 bromo pregnane 1l,B,l7oz,21 triol 3,20 dione 21-acetate; 90c bromo pregnene 1113,21 diol 3,20- dione 21 acetate (and 21esters); 9a bromo pregnane 3a,1l,8,17a,2l tetrol 2O one; 90;bromo-pregnane 305115, 17a, 21- tetrol 20 one 2l-acetate; 9abromo 5pregnene 36, 11B -diol 20 one; 9abromo 5 pregnene 3fl,1l{3,17a,2l tetrol20 one; 90c bromo 5 pregnene 3fi,11,B,17a,2l tetrol 20- one3,2l-diacetate;' 9d bromo 5 pregnene 3:1,115- diol 20 one; 90: bromo 3ethylenedioxy 5 pregnene l1/3,17a,21 triol 20 one; 94x bromo 3,3-dimethoxy 5 pregnene l1,8,17oc,2l triol 20 on e 21- acetate; 90: bromoallo pregna'ne' lll3,17oz,di0l 3,20-

dione; 9a bromo allo pregnane 1118,21 diol 3,20- dione; 9a bromo allopregnane 11B,l7a,21 triol- 3,20 dione; 90c bromo allo-pregnane3a,1lp,l7ot, 21- tetrol 20 one; 90: bromo allo pregnane 3,20-v

dione.

The reaction is preferably carried out in an organic solvent and oneinwhich the steroids are relatively soluble. Thepreferred solvent is analkanol containing from one to eight carbon atoms. When an alkoxide isused the alkanol carbon chainis solvents can be used, such aschloroform, ethylenedichloride, tetrahydrofuran and dioxane, to increasethe solubility of the steroid. When the hydroxides or carbonates areused it may be desirable to use aqueous mixtures to increase thesolubility of the base.

The preferred temperature of the reaction is about normal roomtemperature (20 -30 C.) although higher and lower temperatures can beutilized such as from to 40 C. The reaction proceeds quite rapidly atroom temperature requiring only about one to thirty minutes. The productis conveniently recovered by the addition of an acid such as glacialacetic acid to neutralize the remaining base, and then concentrating ordiluting the mixture with water. The product is extracted from theresulting mixture with an organic solvent, as for example, chloroform.The product can also be precipitated by the addition of water andremoved by filtration.

The following examples are given for the purpose of illustration:

EXAMPLE 1 95,1 IB-oxidot-pregnene-l 7u,2I-diol 3,20 diohe 21 -acetate Amixture of 236 ml. of tetrahydrofuran and 38.0 g. (0.0787 mole) of9a-bromo-4-pregnene-l1/3,17a,21-triol- 3,20-dione 21-acetate is stirredat 24 C. for 30 minutes to effect a homogeneous solution. To thesolution is added 320 ml. of absolute methanol and to a separatoryfunnel 985 ml. of 0.0984 N sodium methom'de in absolute methanol (1.23moles per mole of bromohydrin). The system is purged three times withnitrogen and left under a slight positive nitrogen pressure. To themixture in the flask is added the sodium methoxide solution withstirring over a period of /1 min. Stirring is continued for 4% minutesadditional. At the end of this time the excess sodium methoxide isdestroyed with 55 ml. of glacial acetic acid. A condenser is thenattached to the reactor and the mixture concentrated to 100 ml. in vacuoat 10-15" C. To the mixture is added 320 ml. of water and 800 ml. ofchloroform. The layers are separated and the water layer extracted twicewith 250 ml. portions and twice with 100 ml. portions of chloroform. Thelast extraction is aided by salting out the water layer with 75 g. ofsodium chloride and the last chloroform extract is used to backwash allsubsequent aqueous washing which comprised the following portions; 100ml. of water, twice with 250 ml. portions of 5% sodium bicarbonate, andthen 100 ml. portions of water. The chloroform layer is filtered throughanhydrous magnesium sulfate, concentrated to dryness in vacuo and theresidue treated with 85 ml. of pyridine and 85 ml. of acetic anhydride.The mixture is allowed to stand overnight, then concentrated in vacuo toa thick paste to which is added 300 g. of ice and 100 ml. of ethylacetate. After stirring for one hour 420 ml. of ethyl acetate is addedto extract the water layer. The water layer is extracted twice with 100ml. portions and twice with 80 ml. portions of ethyl acetate. The ethylacetate extracts are combined, washed with water, diulte acid, water, 5%sodium bicarbonate, water and saturated salt solution and filteredthrough anhydrous magnesium sulfate. The filtrate is concentrated todryness in vacuo to produce crystalline material.

EXAMPLE '2 9,9,11 fi-axido-4-prcgnene-l711,21-diol 3,20 dione 21-mtate Asolution consisting of 0.483 g. (one millimole) 'of9a-bromo-4-pregnene-l 1,8, l7a,21-triol3,20-dione 21-acetate, 3.0 ml. oftetrahydrofuran and 1.0 ml. of t-butanol is purged four times withnitrogen. The solution is stirred while adding 1.01 ml. of 1.09 Npotassium t-butoxide in t-butanol. The addition of butoxide turned themixture immediately to a bright pink. The mixture is preferably thesame. Otherhydrous magnesium sulfate.

stirred ten minutes at 25 C. and then quenched with 0.1 ml. of glacialacetic acid which turned the color light amber. The mixture is thenconcentrated to dryness in vacuo. The residue is flushed twice with 3ml. portions of chloroform. A 3 ml. portion of acetic anhydride is addedto the residue after warming with 3 ml. of pyridine and cooling to 25 C.and the mixture allowed to stand overnight. The mixture is concentratedto dryness in vacuo and the residue dissolved with stirring in 20 ml. ofchloroform and 10 ml. of water. The stirring is continued for one hourto decompose any traces of acetic anhydride. After separating the layersthe aqueous phase is extracted with 5 ml. and 3 m1. portions ofchloroform. The combined chloroform phases are extracted with 0.125 Nhydrochloric acid, water, 5% sodium bicarbonate and again with water,and filtered through an- The solution is evaporated to dryness, toafford the crystalline product.

EXAMPLE 3 9B,]IB-oxidol-pregnene-I7a,21-diol 3,20 dione 21 -acetatesired product.

7 EXAMPLE 4 918,11,8-0xido-4-pregnene-1 7a,21-di0l-3,20-di0ne 21-acelate A mixture of 19.80 g. of 9a-bromo-4-pregnene-11fl,l7ot,2l-tricl-3,20-dione 2l-acetate and 791 ml. of tetrahydrofuran wasstirred at 2530 C. until solution was complete. To this solution wasadded with stirring a solution of 6.01 g. of potassium carbonate in 465ml. of water. The mixture was stirred and the temperature was maintainedat 25-30 C. for eight hours. Then 2.0 ml. of glacial acetic acid wasadded to neutralize the excess base. The mixture was concentrated invacuo to ca. 500 ml. and 500 ml. of water was added to the resultingslurry of crystalline material. The slurry was stirred and cooled to 05for one-half hour. The solid product was removed by filtration, washedfree of bromide ion with water and dried, M. P. 196-199. This productwas shown by paper strip chromatography to be free of the startingmaterial and to contain substantially no cortisone acetate.

EXAMPLE 5 A 1.0 g. sample of9oe-bromo-4-pregnene-115,17a,2l-triol-3,20-dione is treated with asolution of barium hydroxide in methanol as described in Example 3. Theproduct is substantially free of cortisone.

Any departure from the above description, which conforms to the presentinvention, is intended to be included within the scope of the claims.

What is claimed is:

1. The process which comprises reacting a 9a-bromollfi-hydroxy-steroidselected from the group consisting of the pregnanes, allopregnanes, andunsaturated pregnane compounds, with a strong base having a pH greaterthan 10 in 0.1 percent aqueous solution to produce the corresponding95,11fl-oxido compound.

2. The process of claim 1 wherein the strong base is a hydroxide.

3. The process of claim 1 wherein the strong base is an alkoxide.

4. The process of claim 1 wherein the strong base is a carbonate.

2,ese,49a

5 5. A process which comprises reacting a 21-acyloxy References Cited inthe file of this patent derivative Of9a-brorno-4-pregnene-11fi,17a,21-trio1-3,20- UNITED STATES PATENTS d 1lone whei em the acyioxy group has the formu 21 2,503,842 Reichstein p1950 5 2,703,799 Bergstrom Mar. 8, 1955 -C 2,705,711 Dodson Apr. 5, 1955wherein R is a hydrocarbon group containing from one to v eight carbonatoms with a strong base having a pH greater OTHER REFERENCES than 10 in0.1 percent aqueous solution to produce 95; Comfofthi Chem. and g- 29,1953, PP-

1lfi-oxidoi-pregnene-17a,21-diol-3,20-dione. 10 PY in Pat

1. THE PROCESS WHICH COMPRISES REACTING A 9A-BROMO11B-HYDROXY-STEROIDSELECTED FROM THE GROUP CONSISTING OF THE PREGNANES, ALLOPREGNANES, ANDUNSATURATED PREGNANE COMPOUNDS, WITH A STRONG BASE HAVING A PH GREATERTHAN 10 IN 0.1 PERCENT AQUEOUS SOLUTION TO PRODUCE THE CORRESPONDING9B,11B-OXIDO COMPOUND.